The C-C chemokine receptor type 5 (CCR5) is a protein found on the surface of white blood cells, including T cells, macrophages, and dendritic cells. Located on chromosome 3, the CCR5 protein acts as a cell-surface receptor, receiving chemical signals from outside the cell. CCR5 is a significant component of the body’s natural defense systems. It is particularly well-known in medical research for its role in allowing the Human Immunodeficiency Virus (HIV) to infect immune cells.
The Standard Function of the CCR5 Gene
The CCR5 protein plays a role in immune surveillance and the inflammatory response. It belongs to a family of receptors that respond to signaling proteins known as chemokines. Chemokines act as chemical beacons, guiding immune cells to sites of inflammation or infection.
Specific chemokines, such as RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4), bind to the CCR5 receptor. This binding triggers a signal inside the white blood cell, instructing it to migrate toward the source. By directing T cells and macrophages, CCR5 ensures immune forces are deployed to eliminate threats and repair tissue damage.
The receptor is highly expressed on memory T cells and macrophages, which are often the first responders and long-term effectors of immunity. The CCR5 protein is routinely expressed by millions of cells in a healthy individual, making its presence a standard aspect of human physiology.
The Protective CCR5-Delta 32 Variant
The CCR5-Delta 32 variant is a genetic alteration that renders the receptor non-functional, providing defense against certain HIV strains. This mutation involves deleting 32 base pairs within the CCR5 gene sequence. This deletion causes a frameshift, introducing a premature stop codon in the genetic instructions.
Consequently, the cell produces a truncated CCR5 protein that cannot anchor itself to the cell surface. The common R5-tropic strain of HIV-1 relies on CCR5 as a co-receptor to gain entry, requiring both the primary CD4 receptor and CCR5 to initiate infection. Without a functional CCR5 receptor, the virus is effectively locked out.
Individuals inheriting one copy of the mutated gene (heterozygous carriers) have fewer functional CCR5 receptors. Although they can still be infected by HIV, they typically experience slower progression to AIDS and lower viral loads. Those inheriting the CCR5-Delta 32 mutation from both parents (homozygous carriers) produce no functional CCR5 protein, granting them strong resistance to infection by R5-tropic HIV strains.
Geographic Distribution of the Variant
The CCR5-Delta 32 allele is concentrated among people of European descent. The highest frequencies are observed in Northern European populations, particularly Scandinavia, Finland, and Russia. In these regions, the allele frequency can reach 16%, with homozygous carriers estimated at 1% of the population.
The frequency declines steadily across Europe toward the Mediterranean. Outside of Europe and Western Asia, the variant is rare or absent in East Asian, African, and Indigenous American populations. This geographic pattern suggests the mutation arose in Europe and was subjected to intense positive selection.
Genetic analysis estimates the age of the CCR5-Delta 32 allele to be between 700 and 5,000 years old. Since HIV emerged recently, theories suggest the selective pressure was a historical plague. Diseases like smallpox or the bubonic plague have been proposed as the ancient agents that favored carriers of the mutation.
Other Health Implications of Carrying the Variant
While the CCR5-Delta 32 mutation protects against R5-tropic HIV, the absence of the functional receptor has other consequences for the immune system. The variant is associated with increased susceptibility to certain viral infections. For instance, homozygous carriers have a higher risk for severe West Nile virus infection and tick-borne encephalitis.
The CCR5 protein also influences recovery from neurological events. Studies suggest the CCR5-Delta 32 mutation may be linked to improved neuroplasticity following a stroke. Conversely, the variant may increase the risk of mortality from certain influenza infections, demonstrating a complex trade-off in immune function.
The receptor’s role in inflammation and cell migration means the variant impacts other medical conditions. The CCR5-Delta 32 allele has been implicated in affecting the outcome of solid organ transplantation and influencing the progression of certain cancers. These varied effects show that the CCR5 protein performs functions extending far beyond its use as an HIV entry point.